Atomoxetine HCl is a selective norepinephrine reuptake inhibitor. It is marketed under the name STRATTERA® for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) and is available in 10 mg, 18 mg, 25 mg, 40 mg, and 60 mg dosage forms. It is a white to practically white solid, which has a solubility of 27.8 mg/ml in water.
Atomoxetine, chemically known as (R)(−)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine, has the following structure:

Atomoxetine, the (R)-(−) enantiomer of tomoxetine, is an aryloxyphenylpropylamine. It is about twice as effective as the racemic mixture and about nine times more effective than the (+)-enantiomer, as disclosed in U.S. Pat. No. 4,018,895 (assigned to Eli Lilly and Co.), EP 0 052 492 (Eli Lilly and Co.), and EP 0 721 777 (Eli Lilly and Co.).
Several processes for synthesizing 3-aryloxy-3-phenylpropylamines are known in the art. For example, U.S. Pat. No. 4,018,895 assigned to Eli Lilly and Co. discloses an aliphatic nucleophilic displacement of N-protected-3-halogen-3-phenylpropylamines by phenols, followed by N-deprotection. U.S. Pat. No. 4,868,344 assigned to Aldrich-Boranes, Inc. relates to the Mitsunobu reaction between 3-hydroxy-3-phenylpropylhalides and phenols, followed by amination of the resulting 3-aryloxy-3-phenylpropylhalides. Tomoxetine is also synthesized by the processes disclosed in U.S. Pat. No. 6,541,668, and WO 00/58262 assigned to Eli Lilly and Co. and WO 94/00416 by Richter Gedeon Vegyeszeti Gyar RT. These patents disclose an aromatic nucleophilic displacement of an aryl halide by 3-hydroxy-3-phenylpropylamines under strongly basic conditions. The nucleophilic aromatic displacement process disclosed in WO 00/58262 comprises reacting N-methyl-3-hydroxy-3-phenylpropylamine with a protected 2-fluoroberizaldehyde to produce tomoxetine after several functional group interconversion steps.
Optical resolution of racemic tomoxetine into (R)-(−)-tomoxetine (atomoxetine) and (S)-(+)-tomoxetine is known in the art. Common techniques include chiral chromatography and fractional crystallization of (S)-(+)-mandelic acid diastereoisomeric addition salts. Because the former is more costly and not optimized for large scale synthesis, the latter is preferred for commercial processes.
EP Patent No. 0 052 492 discloses a process wherein racemic tomoxetine, prepared from N-methyl-3-hydroxy-3-phenylpropylamine, is resolved with (S)-(+)-mandelic acid to obtain (R)-(−)-tomoxetine (S)-(+)-mandelate salt. This process produces a poor yield of about 18%. This process is inefficient and also requires solvents which may be harmful to the environment, such as diethyl ether and dichloromethane. U.S. Pat. No. 6,541,668, assigned to Eli Lilly and Co., discloses an improved resolution process having fewer steps. This process also yields approximately 18% (R)-(−)-tomoxetine (S)-(+)-mandelate (prepared from N-methyl-3-hydroxy-3-phenylpropylamine). However, the optical purity of the (R)-(−)-tomoxetine product is not disclosed.
The poor yields indicate that, in the solvents used, a large amount of the racemic tomoxetine may be unrecovered as (S)-(+)-tomoxetine, the unwanted enantiomer. U.S. Pat. No. 4,777,291, assigned to Eli Lilly and Co., discloses a racemization process from (S)-(+)-tomoxetine to racemic tomoxetine by means of alkyl-alkali metals or alkylamide-alkali metals in tetrahydrofuran or 1,2-dimethoxyethane, preferably butyllithium in tetrahydrofuran. This process requires hazardous solvents and bases unsuitable in a large scale commercial synthesis. Moreover, the patent discloses and one of skill in the art appreciates, that anhydrous media are required in this process.
Epimerizing bases other than alkyl-alkali metals or alkylamide-alkali metals are known in the art for 3-aryloxy-3-phenylpropylamines other than tomoxetine. For example, WO 00/64855 (Eli Lilly and Co.) discloses a racemization process of (S)-fluoxetine into racemic fluoxetine involving a base having a potassium counter-ion in an aprotic highly dipolar solvent.
There is a need in the art for additional processes for optical resolution of racemic tomoxetine in higher yields that can be utilized in large-scale commercial operations. Furthermore, there is also a need for more efficient processes for the epimerization of the unwanted (S)-(+)-enantiomer of tomoxetine.